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DOI: 10.4329/wjr.v9.i1.5
Functional magnetic resonance imaging and the brain: A
brief review
Maggie SM Chow, Sharon L Wu, Sarah E Webb, Katie Gluskin, DT Yew
Maggie SM Chow, Sharon L Wu, DT Yew, School of Biomedical
Science, School of Chinese Medicine, Chinese University of Hong
Kong, Hong Kong, China
Sarah E Webb, Division of Life Science, the Hong Kong
University of Science and Technology, Hong Kong, China
Katie Gluskin, Department of Neuroscience, St. Mary’s College
of Maryland, St Marys City, MD 20686, United States
Author contributions: Chow MSM, Wu SL, Webb SE and Gluskin
K wrote the paper; Yew DT directed the research.
Conflict-of-interest statement: Authors declare no conflict of
interest for this article.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Manuscript source: Invited manuscript
Correspondence to: Dr. Maggie SM Chow, School of Biomedical
Science, School of Chinese Medicine, Chinese University of Hong
Kong, Hong Kong, China. maggiesmchow@gmail.com
Telephone: +852-39434140
Received: June 16, 2016
Peer-review started: June 24, 2016
First decision: August 16, 2016
Revised: September 6, 2016
Accepted: October 22, 2016
Article in press: October 24, 2016
Published online: January 28, 2017
Abstract
Functional magnetic resonance imaging (fMRI) is em­
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World J Radiol 2017 January 28; 9(1): 5-9
ISSN 1949-8470 (online)
© 2017 Baishideng Publishing Group Inc. All rights reserved.
MINIREVIEWS
ployed in many behavior analysis studies, with blood
oxygen level dependent- (BOLD-) contrast imaging being
the main method used to generate images. The use of
BOLD-contrast imaging in fMRI has been refined over
the years, for example, the inclusion of a spin echo pulse
and increased magnetic strength were shown to produce
better recorded images. Taking careful precautions to
control variables during measurement, comparisons
between different specimen groups can be illustrated
by fMRI imaging using both quantitative and qualitative
methods. Differences have been observed in comparisons
of active and resting, developing and aging, and defective
and damaged brains in various studies. However, cognitive
studies using fMRI still face a number of challenges in
interpretation that can only be overcome by imaging
large numbers of samples. Furthermore, fMRI studies of
brain cancer, lesions and other brain pathologies of both
humans and animals are still to be explored.
Key words: Functional magnetic resonance image; Blood
oxygen level dependent imaging; Humans; Pig and rodent
models; Aging; Drug effects; Brain lesions and disease
© The Author(s) 2017. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: We summarize the use of blood oxygen level
dependent-contrast imaging in functional magnetic reso­
nance imaging (fMRI) by introducing and comparing the
various experimental and analysis methods used, as well
as describing the results obtained, and the challenges that
might occur in order to derive a hypothesis for further
studies and exploration. In addition, an overview of fMRI
following sensory stimulation in different specimen groups
in both humans and animals is provided.
Chow MSM, Wu SL, Webb SE, Gluskin K, Yew DT. Functional
magnetic resonance imaging and the brain: A brief review. World
J Radiol 2017; 9(1): 5-9 Available from: URL: http://www.wjgnet.
com/1949-8470/full/v9/i1/5.htm DOI: http://dx.doi.org/10.4329/
wjr.v9.i1.5
 January 28, 2017|Volume 9|Issue 1|
 Chow MSM et al . fMRI study methods, significance and challenges
INTRODUCTION
There have recently been a significant number of be­
havior response analysis studies that have made use
of magnetic resonance imaging (MRI), and in particular
functional magnetic resonance imaging (fMRI). The
majority of these studies make use of blood oxygen
level-dependent- (BOLD-) contrast imaging, which
involves mapping particular regions of a functioning
brain, from the changes in blood oxygen.
BOLD-contrast imaging fMRI has a good enough
spatial resolution for the localization of activated brain
areas and their delineation from neighbouring regions
to be visualised. The voxel representing the area of
activation is usually defined as covering a few million
[1]
neurons . In addition, the BOLD response lags 1 to 2
s behind the stimulus in order for the vascular system
to respond, and in general it peaks at 5 s after the
stimulus. A continuation of the same stimulus would
[1-3]
downregulate the BOLD response . A refractory
period of just a few seconds is frequently inadequate
for BOLD imaging after activation to fade (see below),
depending on whether the mode of activation is motor,
sensory or emotional.
To eliminate noise in the recording, the stimulus
must be repeated several times. This process often
takes a few minutes to complete, and the results
can then be compared across different individuals or
[1,4]
animals . With regards to the latter, rodents, pigs
and monkeys have all been employed in behavior
response analysis studies with BOLD-contrast imaging
[5-9]
fMRI . This technique and thus the quality of images
generated, has been improved by using both a spin
[10]
echo pulse and increasing the magnetic strength .
One region of the brain that is popular for fMRI
mapping due to it being relatively easy to generate a
stimulus, is the sensory part of the brain, including the
[11]
lateral geniculate bodies and the cortex . Over the
last ten years, our group has employed a number of
different inputs of both sensory and motor activations
for fMRI mapping, with some success. These include
chewing, the opposition of the thumb (in humans)
and passively flexing the elbow (in animals). These
different types of activation trigger both the motor
and the sensory systems, such as proprioception and
[12,13]
movement . However, only a limited number of
clinical studies on head injuries, Alzheimer’s disease and
drug use have been documented using this method so
[4]
far .
QUANTIFYING FMRI RESULTS
In the course of performing fMRI and comparing different
specimen groups, it is often necessary to illustrate
comparisons with quantitation. This can be achieved
via a number of methods. For example, the different
levels of oxygen usage are frequently illustrated with
a pseudocolor scale in the images acquired. In the
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commonly used four-color scale, red indicates the highest
level of oxygen uptake, yellow is an intermediate level
of uptake, green indicates the normal level of oxygen,
and blue indicates oxygen levels that are lower than
normal (i.e., down-regulation; Figure 1). Utilizing this
type of color scale, the researcher can easily compare
the volumes of the variously-colored regions either in a
specific part of the brain or globally in the whole brain.
Indeed, some well-funded research laboratories can afford
to purchase software specifically designed to calculate
the morphometry for this purpose. Another method used
for quantitating fMRI images, which is perhaps more
applicable to the smaller, less affluent groups involves
manually counting squares on a simple grid. This is placed
on successive slices of the fMRI image, after which volume
data can be calculated. Though tedious, this method can
yield results that are as accurate as those generated from
expensive software packages.
In addition to quantitative analysis, qualitative eva­
luation is also important, for instance to determine the
specific regions of the brain that are activated during
a particular type of movement. Some of the areas
that are activated might be nonspecific, in which case
the investigator has to carefully consider each site of
activation to determine if any logical deduction might be
obtained. In this respect, at least six individuals, when
available, should be used for every experiment in each
group in order to obtain the n-numbers required to
compare the data statistically. Indeed, in some of our
previous studies, we aimed to recruit at least a dozen
individuals per group. While this was not difficult to
achieve with studies using animals, it was sometimes
difficult to solicit this number of human volunteers or
patients. In addition, we found that fMRI studies are
particularly hard to evaluate when the experiments
involve cognitive changes that might be affected by
emotions. The results of psychometrical tests were
variable in different individuals, especially in those with
neurosis.
fMRI recordings require the subject (whether human
or animal), to perform a particular action in order to
trigger a dynamic uptake of oxygen into the brain. This
is because fMRI recordings are based on the subsequent
increase in oxygen demand from the brain tissue upon
the execution of a certain stimulus, whether it is motor,
sensory or emotional. One memorable case involved
human subjects being asked to repeat a set words in
the correct sequence, which elicited a notable increase
of blood oxygen levels in the inferior frontal area (BA44)
[14]
of the brain . In this study, an uptake of oxygen was
normally elicited after repeated and continuous stimulus,
and the acquisition of the BOLD-contrast image was
usually completed within several seconds after the
stimulation ended (in this case after 6 to 18 s). The
acquisition of subsequent BOLD-contrast images took
[14]
> 1 s per slice, e.g., 1.6 s . The images acquired were
then superimposed on the neuroanatomical image of the
corresponding slices, which facilitated the localization of
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 Chow MSM et al . fMRI study methods, significance and challenges
A B
C D
[14]
the sites of recording . the individual shown in Figure 1, varying levels of activity
FMRI HUMAN CASES AND
DOWNREGULATION
In previous studies, we engaged human volunteers in
active movements such as the opposition of the finger
and thumb, flexion of the arm or mastication (e.g., by
chewing gum)
[12,15]
. In animals, such as pigs, rodents and
monkeys, however, it is often difficult to capture fMRI
images while they are freely and actively moving. Thus,
passive movements tend to be performed instead. These
include flexion and extension of the limbs and visual
stimulation, as well as treatment with drugs.
In order to determine the effect of a specific be­
haviour on the amount of oxygen uptake in particular
regions of the brain using fMRI, images acquired during
movement and at rest must be compared. Indeed,
valid data can be acquired by subtracting the results
recorded at rest from those recorded during movement.
Thus, subjects must be imaged as they perform a
certain type of movement and then again when they
are at rest. It would also be interesting to compare
data from fMRI images acquired at different durations
of rest after movement, as this might provide useful
information regarding changes in the brain that occur
during recovery after movement.
A typical example of a standard fMRI recording is
depicted in Figure 1. Figure 1A indicates a recording that
was acquired when the test subject was at rest. When
we conducted this experiment, we were interested to find
that in a number of individuals, some sporadic activity
occurred in the cortex even at rest. In the recording of
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Figure 1 Functional magnetic resonance imaging image
of different states. A: fMRI of a short term heroin addict at
rest performing no activity and thus have no bodily stimulation.
Note some areas still have high BOLD activity (red); B: fMRI of
a short term heroin addict when performing motor and sensory
activities. Note BOLD image in different regions showing high
upregulation of BOLD (red), medium BOLD activity (yellow).
While blue indicates downregulation of BOLD activities; C: fMRI
of the same individual in (B) at rest after stimulation. There were
still some high activity spots of BOLD after stimulation and at rest
(red); D: fMRI of a long term (over 7 years) addict of heroin at
rest. Many downregulated BOLD spots in the brain (blue). fMRI:
Functional magnetic resonance imaging; BOLD: Blood oxygen
level dependent.
were registered in the motor, sensory and visual areas
of the brain, as well as in the midline of the cortex. Upon
stimulation (achieved by thumb and finger opposition),
clear and intensive reactions became apparent in the
BOLD-contrast images, but these were limited to the
motor and sensory areas alone (Figure 1B). Figure 1C
depicts the corresponding fMRI image from the same
individual following two minutes of stimulation and then
one-minute of rest. It is still possible to recognise some
residual increased brain activity in the post stimulation
resting state. These figures demonstrate the importance
of the timing used for the evaluation and comparison
of data, as well as the use of the same individual for
collecting corresponding sections in each series.
Another comparison method involves depicting of
all the active sites of BOLD-contrast fMRI images in the
whole brain both at rest and during stimulation. Both
of these different methods of comparison are useful in
their own way, with the comparison of corresponding
slices providing a quantitation of comparison on specific
sites, whereas the whole brain images provide a global
picture of all the active sites.
In addition to recording the uptake of blood oxygen
levels into the brain, the downregulation of blood oxygen
has also recently been imaged by fMRI, in order to
evaluate subjects with brain damage or brain defects.
Figure 1D is an fMRI slice of the brain of long-term
heroin addict. The large numbers of blue spots indicate
regions of the brain where the blood oxygen levels are
lower than normal (as described above, green indicates
normal levels of oxygen). In the drug addict’s brain, the
blood oxygen was low (i.e., downregulated) in the grey
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 Chow MSM et al . fMRI study methods, significance and challenges
matter, and also in the fibers, especially those in the
corpus callosum (Figure 1D). These data confirm those
acquired from ordinary MRI of addicts on abusive drugs,
[16]
which also demonstrated degenerative sites , especially
degenerative fibers or grey matter in the cortex, or in
groups of nuclei in the cerebellum.
THE USE OF FMRI TO STUDY BRAIN
DEVELOPMENT AND DISEASE
fMRI recordings are useful for evaluating the changes
in the overall activity of specific brain regions, not only
in adults, but also in developing and aging animals.
For example, in one study, fMRI was conducted in the
neonatal pig. At this stage of development the brain is
relatively immature, and it was shown that stimulation
of either sensory or motor activities in the body elicited
[7]
a wide global and non-discrete response in the brain .
Several months later, stimulation of the same activities
only produced induced BOLD responses in discrete
and related areas of the brain. This example clearly
shows that nonselective responses were elicited in
the immature brain, whereas in the maturing or fully
mature brain, the particular neuronal groups that fired
were specific to the related functioning areas. The
same type of global nonspecific firing observed in the
fMRI of the immature brain can also be observed in
some brain diseases such as schizophrenia and bipolar
disorders. Follow-up cytochemical and histological
studies con­ducted with the pig concluded that during the
develop­ment and maturation of the brain, superfluous
pathways were pruned significantly, and the number
of inhibitory contacts that refine the specificity of each
pathway of the brain increased. This study and others,
demonstrated the usefulness of utilizing BOLD and fMRI
for understanding psychiatric and neurological diseases,
and they facilitated the collection of pathological
specimens along the way at the same time. The use of
fMRI imaging in conjunction with cytochemistry and/or
classical pathohistological techniques has the potential
to become a very powerful tool to help with the analysis
of neurological diseases and mental disorders.
In addition to imaging the developing brain, fMRI
can be applied to the aging brain. In a study employing
humans of different ages (i.e., young, middle-aged
and old), BOLD-contrast imaging of fMRI was recorded
in each group as they performed the same motor
[12]
activities . The results obtained were interesting and
significant. More brain area activations were recorded in
individuals in the “old” group (i.e., around 70 years of
age), when compared with individuals from the young
and middle-aged groups as they conducted the same
motor activity. It was concluded that the older brain
is less efficient, and so larger areas are required to
achieve a certain job. To substantiate this proposition,
it was necessary to obtain a similar result in animals.
As mentioned previously, specific active movements
are a challenge to initiate in animals but passive
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movements are easier to control although the results
obtained are more difficult to interpret. Therefore, in
one a series of experiments we conducted, we used
sensory stimulation in order to evaluate the aging hy­
pothesis by applying a weight to the tail of rodents of
[17]
different ages . The results obtained with the rodents
complimented those of the human studies in that the
sensory stimulus triggered increased blood oxygen
levels in larger areas of the brains of the older animals
than in the young groups. It is therefore tempting to
conclude that larger areas of the brain are recruited in
the aging groups than in the young groups, to conduct
the same functional activity. Perhaps this is due to
brains being less efficient overall on aging. On the other
hand, it is also possible that on aging it is normal for
additional areas of the brain to be used to engage in
activities. This would therefore illustrate the plasticity of
the brain during aging rather than simply a reduction in
the efficiency over time.
CHALLENGES AND FUTURE DIRECTIONS
FOR FMRI STUDIES
Cognitive studies using fMRI are extremely important,
but the results can be a challenge to interpret. The
main difficulties lie in the psychometric nature of the
individual to be recorded. For instance, some individuals
are very anxious and when they are asked unrelated
questions, this elicits responses in areas of the brain
that are not normally engaged. Interpretation of data
therefore depends on being able to collect a large
enough number of samples to be able to exclude false
positive results. fMRI imaging has largely been con­
ducted with humans (including normal individuals,
patients, addicts, and aged individuals), as well as in
animal models of addiction and aging
[18,19]
. In the case
of patients with various diseases, the way forward for
fMRI and its potential are largely still under-explored.
However, it might be very insightful to find out how
areas of the brain areas react in patients with brain
cancer, for example. It would also be interesting to
explore any changes that might occur in focal path­
ological areas and in normal areas surrounding the
pathology; as well as what changes take place in the
brain as the disease progresses. These are just a few
of the studies that might be conducted using BOLD-
contrast fMRI.
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P- Reviewer: Gao BL, Pan HC, Takahashi H S- Editor: Kong JX
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